Medical therapies frequently depend on the ability to control the function of specific proteins in vivo, thereby altering the disease state. For example, various recombinant genetic treatments have been used to supplement or replace proteins which are absent or insufficiently produced due to disease. Conversely, many drug therapies rely on the inhibition of protein function which is elevated in the disease state, and their discovery can depend on measurement of the effectiveness of a drug candidate's inhibition. Specifically, in vitro and in vivo assays (Cell based or animal models) are routinely developed to identify new drug candidates, and optimize structures based on inhibitory data. These assays are relied upon for predicting the effectiveness of drug treatments while minimizing unwanted interactions with non-target proteins.
The discovery of protein-based targets in an organism and the effect of regulation of this target on a disease state has become a well-accepted method for identifying molecules that affect them; see for example, S. L. Schreiber, Chem. Eng. News. 2003, 81(9), 51-61. These molecules provide leads to new drug classes and eventually to useful pharmaceuticals substances.
Many protein targets are now known or implicated in medical research and often routinely used in drug discovery research. However, it is expected that many more remain to be discovered and understood. Several methods have been described which are used in this discovery effort, such those described in L. A. Banaszynski et al., Nat. Med., 2008, 14 (10), 1123-1127, and references therein. These include the use of hosts in which specific genes have been silenced, i.e., knockouts, and observation of the resulting effect in vivo. Also known is the so called Cre-loxP system (A. D. S. Ryding et al., J. Endrocrinol., 2001, 171, 1-14 and R. Kuhn et al., Science, 1995, 269, 1427-1429.) In the 2008 Banasynski 2008 reference there is reported a general system useful for studying the function of specific proteins in a more directed and precise manner. A gene sequence coded for the protein of interest and as well as a small, destabilizing protein (known as FKBP L106P) is engineered and inserted in to a cell line of interest. The fused protein, although expressed, becomes destabilized, but is rescued by addition of a stabilizing ligand which binds to the destabilizing FKBP L106 domain. The amount of protein available can thus be controlled by the amount of stabilizing ligand added to the cell or organism in which the protein is expressed. The ability to effect stabilization has been also demonstrated in cultured cells. (Banaszynski et al., 2006). The applicability of the technique to living organisms was demonstrated by the successful introduction of a cytokine IL-2/FKBP L106P sequence into the HCT116 cancer cell line, and the formed tumor was introduced by xenograph into mice. The amount of IL-2 in the animal was dependent on the amount of stabilizing ligand (designated as Shield-1) introduced into the mouse. Demonstrating the ability to control IL-2 (Interleukin-2) is significant because it is a protein useful in recombinant gene therapies for treating cancer.
Stabilizing ligands, (Shield-1 and Shield 2) and their binding behavior to the FKBP L106P destabilizing domain, are specifically described by J. S. Grimley et al., Bioorg. Med. Chem. Lett., 2008, 18, 759-761.

To broaden the applicability of this research tool, stabilizing ligands other than Shield-1 or Shield-2, that do not materially diminish the binding affinity to the FKBP L106P destabilizing domain, but have advantageous physicochemical properties would be useful. Because of the variety of physiological conditions under which proteins may exist in vivo (variable pH, exposure to proteases and other metabolizing enzymes), ligands with improved exposure characteristics, i.e., pharmacological properties would be useful. Such characteristics would be, for example, improved aqueous solubility and greater chemical stability, i.e., resistance to hydrolysis or digestion. These ligands may lead to a more convenient route of administration such as intra-venous or oral. In addition, ligands that are readily accessible by straightforward synthetic methods would be desirable.